Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder that may be caused by epigenetic and/or genetic factors. For example, the epsilon allele encoded by the apolipoprotein E (APOE) gene on chromosome 19 increases the risk of sporadic AD, while head trauma is an environment risk factor for sporadic AD. Further familial, AD (FAD) is caused by autosomal dominant mutations in the amyloid precursor protein (APP) gene on chromosomal 21, as well as in genes encoding two different membrane spanning proteins known as Presenilin 1 (PS-1) and Presenilin 2 (PS-2) on chromosome 14 and 1, respectively, while trisomy 21 (Down's syndrome) patients developed extensive AD-like pathology by age 40. However, other AD genes and epigenetic risk factors undoubtedly exist. Despite the genotypic and phenotypic heterogeneity of AD, elderly patients with a progressive dementia are assigned a diagnosis of AD when postmortem examination reveals numerous telencephalic Abeta-rich senile plaques (SPs) and tau-rich neurofibrillary tangles (NFTs). Thus, we hypothesize that SPs and NFTs represent part of a final common pathway leading to neuron loss and dementia in AD, and that head trauma augments this process. Indeed, head trauma could increase the risk for AD by acting synergistically (i.e. as a "second hit" with AD pathologies. Since animal models that recapitulate AD-like SPs and NFTs enable rigorous tests of the hypothesis, the Aims of Project 4 are designed to accomplish this goal by: 1) Inducing or augmenting the formation of AD-like SPs in existing transgenic mice that over-express mutant human APP and develop age-related SP-like lesions by subjecting young and aged mice to traumatic brain injury (TBI); 2) Developing transgenic mice that over-express human tau and accumulate tau in neuronal perikarya; 3) Cross-breeding human tau transgenic mice with mutant human APP transgenic mice described above in Aim 1; 4) Inducing or augmenting the formation of AD-like SPs, perikaryal tau accumulations and NFTs in the tau and crossed transgenic mice described above in Aim 3 by subjecting young and aged mice to TBI; 5) Determining modes of neuron degeneration in regions of the brain with and without AD-like SPs, perikaryal tau accumulations and NFTs before and after TBI or sham treatment of the transgenic mice described in Aims 1-3 using biochemical, morphological and "single cell mRNA profiling" methods.